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Regulation of pathogenicity of Th2/Th9 cells by IRF1 in Asthma

Funding: Else-Kröner-Fresenius Stiftung (EKFS), 2015_A232 Subproject 2

Th2 and Th9 cells have been shown to cause allergic airway inflammation and inflammatory bowel disease (IBD) in mouse models. Accordingly, in human asthma and IBD, increased amounts of IL-4, IL-5, IL-13 and IL-9 are detectable. Hence, analysing factors influencing the development of Th2 and Th9 cells will provide better understanding of their effector role across these immunopathologies. 

The Th1-derived cytokine IFN-g suppresses IL-4 and IL-9 production in Th cells and also inhibits allergic airway inflammation. The transcription factor (TF) Interferon Regulatory Factor (IRF) 1 is upregulated by IFN-g and suppresses IL-4-production. Our preliminary data show that IRF1 also inhibits IL-9 production. Thus, IRF1-deficient cells displayed diminished sensitivity to IFN-g-mediated suppression. Instead, they co-produced increased amounts of Th2 and Th9 cytokines as compared to canonical Th9 cells, which fail to secrete the Th2 cytokines, suggesting a highly pathogenic Th2/Th9-hybrid phenotype. 

Here, we plan to analyse the contribution of IRF1 to the Th2/Th9 differentiation check-points at the single cell level in vitro and during allergic asthma and IBD, using fluorescence- and mass spectrometry - based cytometry as well as transcriptome analysis. We particularly aim to define markers of highly pathogenic Th2/Th9 cells, which could be used as targets for therapeutic depletion during asthma and/or IBD.

Figure 1. Mass cytometry-based identification of a unique T-cell signature predicting childhood AA

CyTOF analysis was applied to systematically characterize T-cell subpopulations in childhood AA. A dysregulated Treg compartment was linked to a novel TIGIT+ICOS+ Th2 cluster and to memory CD8+ T-cells and, to clinical parameters. These findings give implications for disease pathophysiology. Abbreviations: AA, allergic asthma, CM, central memory; CyTOF, cytometry by time of flight; eTreg effector Treg; nTreg, naïve Treg.